Targeted delivery of therapeutic agents as a means for treating cancer has been proposed by many authors. Conceptually, the idea is to deliver a toxic substance selectively to the cancer cells, thus reducing the general toxicity to the patient. This is theoretically possible, since many cancer cell types have been found to have increased levels of hormone receptors and similar receptors. For example, breast cancer cells may have elevated levels of HER2 receptors or estrogen receptors which result in hormone-stimulated growth of cancer cells, while androgen receptors are required for growth of many prostate cancers and mutation of the androgen receptors frequently occurs in advanced prostate cancer.
Hormone receptors have been used in studies on the feasibility of using direct targeted chemotherapy agents to certain classes of cells. Thus, for example, Lam et al., Cancer Treatment Reports 71: 901–906 (1987) have reported on estrogen-nitrosourea conjugates as potential cytotoxic agents against human breast cancer, while Brix et al., J. Cancer Res. 116: 583–539 (1990) have reported on studies of the use of androgen-linked alkylating agents as antineoplastic agents. See also, Eisenbrand et al., Acta Oncologica 28: 203–211 (1989). Myers and Villemez, Biochem. Biophys. Res. Commun. 163: 161–164 (1989) have disclosed the possibility of utilizing luteinizing hormone coupled to a truncated diphtheria toxin.
Geldanamycin (GM) and herbimycin A (HA) are natural benzoquinoid ansamycin antibiotics. Uehara, et al., Mol. Cell. Biol. 6, 2198–2206 (1986). This class of drugs binds to a specific pocket in the chaperone protein hsp90. Stebbins, C. E. et al., Cell 89, 239–250 (1997); Prodromou, et al., Nat Struct Biol 4, 477–482 (1997). Occupancy of this pocket by the drug leads to the degradation in the proteasome of a subset of proteins that require hsp90 for conformational maturation. Schneider, et al., Proc. Natl. Acad. Sci. (USA) 93, 14536–14541 (1996); Csermely, et al., Pharmacol Ther 79, 129–168 (1998); Scheibel, et al., Biochem Pharmacol 56, 675–682 (1998). These include the HER- and insulin-receptor family of transmembrane tyrosine protein kinases, Raf serine kinase and steroid receptors. Addition of GM to tumor cells leads to an Rb-dependent G1 growth arrest and apoptosis. HER-kinases are among the most sensitive targets of GM and tumor cell lines in which HER2 is overexpressed are inhibited by especially low concentrations of the drug. Miller, et al., Cancer Res 54, 2724–2730 (1994); Schnur, et al., J. Med. Chem. 38, 3806–3812 (1995); Hartmann, et al., Int J Cancer 70, 221–229 (1997). These findings imply that GM and related drugs may be useful in the treatment of a variety of tumors. An analog of GM, 17-allyaminoGM, will soon be studied in phase I clinical trials. However, the number of important signaling molecules that are affected by ansamycins suggests that they may have untoward toxicity. In addition, benzoquinoid antibiotics can induce the selective degradation in vivo of receptors, including estrogen, androgen and progesterone receptors. International Patent Publication No. WO98/51702 discloses the ability of compositions comprising an ansamycin antibiotic or other hsp90 binding moiety and a targeting moiety which specifically binds to a target protein to stimulate the selective degradation of such target proteins, and the use of such compositions as chemotherapy agents.
HER-family transmembrane receptor tyrosine kinases play an important role in transducing extracellular growth signals and when activated can be oncogenic. Tzahar, et al., Biochim Biophys Acta 1377, M25–37 (1998); Ross, et al., Stem Cells 16, 413–428 (1998). Over-expression of HER1 and HER2 occurs in a variety of human malignancies. Amplification of the HER2 gene is a common event in human breast and other carcinomas and, in breast cancer, is associated with a poor prognosis. HER1 and HER2 are attractive targets for therapeutic development. Antibodies against each of these receptors have been shown to have antitumor effects in animal models. Fan, et al., Curr Opin Oncol 10, 67–73 (1998). Recently, an anti-HER2 antibody was shown to be effective in the treatment of breast cancers in which the HER2 protein is overexpressed. Ross et al., supra; Pegram, et al., J Clin Oncol 16, 2659–2671 (1998). However, therapeutic effects were seen in only a minority of patients and were usually short-lived. It is not known whether this is due to inefficient inhibition of the target by the antibody, but clearly other more effective methods for HER2 inhibition are needed.
Thus, notwithstanding efforts to date, there remains a substantial need for compositions which can be utilized to selectively target and degrade HER-family tyrosine kinases which can be used as chemotherapy agents in the treatment of HER-expressing cancers, including Her2 positive breast cancer. It is an object of the present invention to provide such compositions.
It is a further object of the present invention to provide a method for the treatment of Her-positive cancers.